Very little is known about chronic, long-term actions of endogenous proinflammatory cytokines on basic biobehavioral processes, particularly neuroimmune-mediated sickness behavior, motor function, fatigue and memory. We and others have documented a significant rise in the proinflammatory cytokines IL-6, IL-1 and TNF in both the periphery and brain of healthy aging mice. We hypothesize that this chronic elevation in proinflammatory cytokines is responsible for performance deficits in multiple biobehavioral processes in aged animals. We have established that IL-6 increases and IL-10 decreases significantly in the brain and plasma of healthy aging mice. These changes are associated with reduced hippocampal-dependent spatial memory and motor function (as assessed by locomotor activity and treadmill running). We have also shown that two important aspects of sickness behavior, immobility and social investigation following i.c.v, injections of either LPS or IL-1, are ameliorated in IL-6 knockout mice. We postulate that the normal, chronic, age-associated rise in IL-6, IL-1 and TNF impacts numerous biobehavioral processes, as assessed by an increase in sickness-related behaviors (diminished social investigation, spatial memory loss) and a reduction in motor function (fatigue on a treadmill, alternations in a 4-arm plus maze, stationery rod). In Objective 1, we will test the hypothesis that all of these age-associated biobehavioral variables are attenuated in Toll-like receptor-4 and NF-KappaB p50 knockout mice but are exacerbated in mice deficient in IL-10. Objective 2 will use IL-6- deficient mice and cytokine-specific antibodies to define intracellular substrates that lead to age-associated reductions in these biobehavioral events. Objective 3 will expand our exciting findings that IGF-I, a growth factor that behaves as an anti-inflammatory cytokine and declines during aging, counteracts age-associated biobehavioral deficits. Finally, Objective 4 will utilize a well-defined model that is very likely to explain the molecular events that are directly responsible for biobehavioral performance deficits in both muscle and brain. These experiments will use both in vitro and in vivo approaches and are needed to understand how chronic, long-term elevations in proinflammatory cytokines impair important biobehavioral processes.